The present invention relates to a method for inhibiting hair loss and/or promoting hair growth in chemotherapy patients employing the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile or pharmaceutical compositions containing same.
Potassium channel openers such as minoxidil (Upjohn), pinacidil (Lilly) and diazoxide (Shiseido and Schering-Plough) are known for their hair growth stimulating activity. Thus, U.S. Pat. Nos. 4,596,812 and 4,139,619 disclose use of minoxidil in the treatment of male pattern baldness, alopecia areata and balding in females. U.S. Pat. No. 4,057,636 discloses pinacidil. DE 3,827,467A discloses combinations of minoxidil and hydrocortisone or retinoids.
U.S. Pat. No. 5,011,837 to Atwal et al discloses aryl cyanoguanidines which possess potassium channel activating activity and are useful therapy for hypertension and other cardiovascular disorders, for various central nervous system disorders, kidney and urinary problems as well as for the promotion of hair growth, for example in the treatment of male pattern baldness (alopecia). These aryl cyanoguanidines have the structure 
and its possible tautomers 
and 
including pharmaceutically acceptable salts, wherein
R1 is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl;
R2 is 
R3 and R4 are each independently selected form xe2x88x92R2, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halo, alkoxy, xe2x80x94NHalkyl, xe2x80x94N-(alkyl)2, xe2x80x94S-alkyl, xe2x80x94O-aryl-alkyl, xe2x80x94S-arylalkyl or xe2x80x94S-aryl, xe2x80x94O-aryl, xe2x80x94NHaryl-alkyl, or R2 and R3 taken together are a group which form a ring with the two carbon atoms to which they are attached, which group is selected from 
wherein
m=1 or 2,
n=3-5,
p=2-4,
X is 0, NR5, CH2; and
R5 is hydrogen or R1.
Example 1 of U.S. Pat. No. 5,011,837 discloses the preparation of 4-[[(cyanoimino)-[(1,2,2-trimethylpropyl)amino]benzonitrile 
in the form of its racemic mixture.
U.S. Pat. No. 6,013,668 discloses a method for promoting hair growth in humans employing the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)-amino]methyl]amino]benzonitrile.
PCT Application WO 92/02225 discloses a combination of a potassium channel opener and a 5-xcex1-reductase inhibitor for promoting hair growth.
PCT Application WO 92/09259A discloses use of an androgen blocker and a potassium channel activator for stimulation of hair growth.
PCT Application WO 96/29988 discloses a topical formulation containing minoxide or minoxidil in combination with a testosterone 5-xcex1 reductase inhibitor.
PCT Application WO 94/18936 discloses a method for promoting hair growth employing a vasodilator such as minoxidil in combination with estradiol and/or a 5-xcex1-reductase inhibitor.
The use of minoxidil in cancer patients to decrease the duration of baldness caused by chemotherapy is disclosed by Duvic, M. et al, xe2x80x9cA randomized trial of minoxidil in chemotherapy-induced alopeciaxe2x80x9d, J. Am. Acad Dermalol 1996; 35:74-8. Duvic et al disclose that in patients treated with fluorouracil, doxorubicin and cyclophosphamide a 2% topical solution of minoxdil administered during chemotherapy and 4 weeks thereafter, did not prevent alopecia but did decrease period of baldness.
Rodriguez, R. et al xe2x80x9cMinoxidil (Mx) as a prophylaxis of doxorubicin-induced alopeciaxe2x80x9d, Annals of Oncology 5:769-770, 1994 discloses that a 2% topical solution of minoxidil was not effective in preventing doxorubicin-induced alopecia.
Hussein, A. M., xe2x80x9cProtection Against Cytosine Arabinoside-Induced Alopecia By Minoxidil In A Rat Animal Modelxe2x80x9d, Int. J. Dermatol. Vol. 34(7); 470-3, 1995 discloses that minoxidil, when injected locally, offered good local prevention against 1-B-D-arabinofurano-sylcytosine but not cyclophosphamide-induced alopecia.
In accordance with the present invention, a method is provided for preventing or inhibiting chemotherapy-induced or radiation therapy-induced hair loss wherein a therapeutically effective amount of the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)-amino]methyl]amino]benzonitrile, (hereinafter xe2x80x9cthe (R)-enantiomerxe2x80x9d) is administered to a human or other mammal.
In addition, in accordance with the present invention, a method is provided for promoting hair growth in a patient undergoing chemotherapy or radiation and/or having chemotherapy-induced hair loss or radiation-induced hair loss, wherein a therapeutically effective amount of the (R)-enantiomer is administered to the patient.
In carrying out the above methods, the (R)-enantiomer will be administered to the patient prior to and/or simultaneously with and/or subsequent to chemotherapy and/or radiation therapy.
The above (R)-enantiomer of the invention has the structure I 
The (R)-enantiomer will preferably be in substantially pure form, that is, will be at least 99% pure (R)-enantiomer and will at most contain 1% (S)-enantiomer.
The method of the present invention also includes the use of pharmaceutical compositions containing the (R)-enantiomer and a pharmaceutically acceptable carrier therefor.
The (R)-enantiomer may be prepared as described in U.S. Pat. No. 6,013,668 which is incorporated herein by reference.
The (R)-enantiomer may be administered by itself or may be administered prior to, simultaneous with or after the antineoplastic agent used in chemotherapy, or prior to simultaneously with or after radiation therapy. In a preferred embodiment of the present invention, the (R)-enantiomer is administered prior to the antineoplastic agent or radiation therapy.
As used herein, the term xe2x80x9csimultaneousxe2x80x9d means that the antineoplastic agent or radiation therapy and the (R)-enantiomer are administered within 24 hours, preferably 12 hours, more preferably 6 hours, and most preferably 3 hours, of each other.
The chemotherapeutic agent which may be employed with the (R)-enantiomer may include any of the antineoplastic agents listed in the Physician""s Desk Reference.
As used herein, the phrase xe2x80x9cradiation therapyxe2x80x9d includes, but is not limited to, x-rays or gamma rays which are delivered from either an externally applied source such as a beam or by implantation of small radioactive sources.
As used herein, the phrase xe2x80x9cantineoplastic agentxe2x80x9d refers to compounds which prevent cancer cells from multiplying. In general, the antineoplastic agents of this invention prevent cancer cells from multiplying by: (1) interfering with the cell""s ability to replicate DNA, or (2) inducing apoptosis in the cancerous cells.
Examples of antineoplastic agents which are suitable for use in the methods of this invention include, but are not limited to, microtuble-stabilizing agents such as the taxanes, for example, paclitaxel (also known as Taxol(copyright)), docetaxel (also known as Taxotere(copyright)), 7-O-methylthio-methylpaclitaxel (disclosed in U.S. Pat. No. 5,646,176), 3xe2x80x2-tert-butyl-3xe2x80x2-N-tert-butyloxycarbonyl-4-deacetyl-3xe2x80x2-dephenyl-3xe2x80x2-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (disclosed in U.S. Ser. No. 60/179,965 filed on Feb. 3, 2000, and example 17 herein), C-4 methyl carbonate paclitaxel (disclosed in WO 94/14787), the epothilone, such as epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]hepta-decane-5,9-dione (disclosed in WO 99/02514), [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-di-hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabi-cyclo[14.1.0]-heptadecane-5,9-dione (disclosed in U.S. Ser. No. 09/506,481 filed on Feb. 17, 2000, and examples 7 and 8 herein), and derivatives thereof; microtuble-disruptor agents; alkylating agents; anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers; growth inhibitors; hormonal/antihormonal therapeutic agents; and haematopoietic growth factors.
Other classes of antineoplastic agents suitable for use in the method of the present invention include, but are not limited to, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, discodermolide, the pteridine family of drugs, diynenes, aromatase inhibitors, and the podophyllotoxins. Particularly useful members of those classes not previously mentioned include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, and the like. Other useful antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosfamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, and interleukins.
In carrying out the method of the invention, the (R)-enantiomer may be formulation with other hair growth promoting compounds such as the potassium channel openers minoxidil (Upjohn) and/or diazoxide (Shiseido and Schering-Plough), as well as cromakalim and pinacidil; a 5-xcex1-reductase inhibitor such as finasteride (Merck""s Proscar(copyright)), terazosin HCl (Abbott""s Hytrin(copyright)), or doxaosin mesylate (Pfizer""s Cardura(copyright)); and/or an androgen blocker such as 4-(5-methoxyheptyl)-hexahydro-2(1H)-pentalenone as disclosed in PCT Application WO 92/09259A, vasoconstrictors such as betamethasone dipropionate, corticosteroids such as hydrocortisone, and scopolamine, and cyproterone acetate.
The (R)-enantiomer may be administered via topical, oral, parenteral or rectal routes as described in U.S. Pat. No. 5,011,837 (incorporated herein by reference), with topical being preferred, to humans or other mammals such as dogs and cats prior to, simultaneous with and/or subsequent to chemotherapy and/or radiation therapy. Thus, the (R)-enantiomer in suitable topical formulations is applied to the skin region where hair growth is desired and/or where hair loss is to be inhibited.
Typical topical formulations for use herein will include conventional ointments, creams, lotions, waxes, gels, pastes, jellies, sprays, aerosols and the like in aqueous or non-aqueous formulations. Examples of suitable topical formulations are disclosed in U.S. Pat. Nos. 4,139,619 and 4,596,812 which are incorporated herein by reference.
The (R)-enantiomer will be used in an effective amount, that is, in an amount sufficient to inhibit hair loss during chemotherapy and/or radiation therapy and/or promote hair growth during and/or subsequent to chemotherapy and/or radiation therapy, such that hair growth is increased or produced. A typical topical composition will include from about 0.01 to about 15% by weight, preferably from about 0.1 to about 10% by weight of the composition.
The topical formulations containing the (R)-enantiomer of the invention can be applied to the area to be treated such as the scalp in humans, by spraying, dabbing or swabbing to deliver the enantiomer to the region of the hair follicle. The formulations will be applied to the area of treatment on a routine basis prior to, during and subsequent to chemotherapy and/or radiation therapy, at least once daily, and preferably two or more times daily.
The accompanying Figure is a graph showing the effect of a once daily application of each of the (R)- and (S)-enantiomers described herein on hair growth in male C3H mice.
The following Example describes the preparation of the (R)-enantiomer and the (S)-enantiomer.